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RNA world easier to make

An elegant experiment has quashed a major objection to the theory that life on Earth originated with molecules of RNA.

John Sutherland and his colleagues from the University of Manchester, UK, created a ribonucleotide, a building block of RNA, from simple chemicals under conditions that might have existed on the early Earth.

The feat, never performed before, bolsters the 'RNA world' hypothesis, which suggests that life began when RNA, a polymer related to DNA that can duplicate itself and catalyse reactions, emerged from a prebiotic soup of chemicals.

"This is extremely strong evidence for the RNA world. We don't know if these chemical steps reflect what actually happened, but before this work there were large doubts that it could happen at all," says Donna Blackmond, a chemist at Imperial College London.

Molecular choreography

An RNA polymer is a string of ribonucleotides, each made up of three distinct parts: a ribose sugar, a phosphate group and a base - either cytosine or uracil, known as pyrimidines, or the purines guanine or adenine. Imagining how such a polymer might have formed spontaneously, chemists had thought the subunits would probably assemble themselves first, then join to form a ribonucleotide. But even in the controlled atmosphere of a laboratory, efforts to connect ribose and base together have met with frustrating failure.

The Manchester researchers have now managed to synthesise both pyrimidine ribonucleotides. Their remedy is to avoid producing separate ribose-sugar and base subunits. Instead, Sutherland's team makes a molecule whose scaffolding contains a bond that will turn out to be the key ribose-base connection. Further atoms are then added around this skeleton, which unfurls to create the ribonucleotide.

"We had a suspicion there was something good out there, but it took us 12 years to find it."

John Sutherland University of Manchester

The final connection is to add a phosphate group. But that phosphate, although only a reactant in the final stages of the sequence, influences the entire synthesis, Sutherland's team showed. By buffering acidity and acting as a catalyst, it guides small organic molecules into making the right connections.

"We had a suspicion there was something good out there, but it took us 12 years to find it," Sutherland says. "What we have ended up with is molecular choreography, where the molecules are unwitting choreographers." Next, he says, he expects to make purine ribonucleotides using a similar approach.

The start of something special?

Although Sutherland has shown that it is possible to build one part of RNA from small molecules, objectors to the RNA-world theory say the RNA molecule as a whole is too complex to be created using early-Earth geochemistry. "The flaw with this kind of research is not in the chemistry. The flaw is in the logic - that this experimental control by researchers in a modern laboratory could have been available on the early Earth," says Robert Shapiro, a chemist at New York University.

Sutherland points out that the sequence of steps he uses is consistent with early-Earth scenarios - those involving methods such as heating molecules in water, evaporating them and irradiating them with ultraviolet light. And breaking RNA's synthesis down into small, laboratory-controlled steps is merely a pragmatic starting point, he says, adding that his team also has results showing that they can string nucleotides together, once they have formed. "My ultimate goal is to get a living system (RNA) emerging from a one-pot experiment. We can pull this off. We just need to know what the constraints on the conditions are first."

Shapiro sides with supporters of another theory of life's origins – that because RNA is too complex to emerge from small molecules, simpler metabolic processes, which eventually catalysed the formation of RNA and DNA, were the first stirrings of life on Earth.

"They're perfectly entitled to disagree with us. But having got experimental results, we are on the high ground," says Sutherland.

"Ultimately, the challenge of prebiotic chemistry is that there is no way of validating historical hypotheses, however convincing an individual experiment," points out Steven Benner, who studies origin-of-life chemistry at the Foundation for Applied Molecular Evolution, a non-profit research centre in Gainesville, Florida.

Sutherland, though, hopes that ingenious organic chemistry might provide an RNA synthesis so convincing that it effectively serves as proof. "We might come up with something so coincidental that one would have to believe it," he says. "That is the goal of my career."

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